Malignant pleural mesothelioma (MPM) is a rare and aggressive disease with poor prognosis. MPM is classified into three histological subtypes: epithelioid, biphasic, and sarcomatoid. This classification does not account for survival differences and intratumor heterogenity, especially for epithelioid MPM (eMPM) that is the most common subtype. The aim of this study is to evaluate transcriptomic differences of eMPM based on prognostic classes. MPM patients with available FFPE tissue were retrospectively and prospectively enrolled at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan and Azianda Sanitaria Universitaria Giuliano Isontina of Trieste between 2006 and 2021 within the granted Italian MOH project, GR-2016-02361229. RNA was automatically extracted and quantified using a fluorometer. Transcriptome was assessed through the 3’DGE method. Patients were divided into three groups based on months (mo) of survival: long survivors (LS) > 36 mo, normal survivors (NS) > 12 and ≤ 36 m, and short survivors (SS) ≤ 12 mo. Evaluation of differential gene expression (GED) between SS and LS was performed for single genes. Moreover, in the same setting, a gene set enrichment analysis (GSEA) was also performed. 125 eMPM cases were enrolled, 90 (72%) males and 35 (28%) females, with a median age at diagnosis of 72 years. At a median follow-up of 88 mo, the median overall survival (OS) was 21 mo. Among patients, 33 were LS, 54 were NS, and 38 were SS. GED showed higher levels of NUF2 and TUBB3, genes involved in the epithelial-mesenchimal-transition (EMT), and a lower expression of ADH1B, PLA2G2A, genes related to metabolism, in SS. EMT, metabolism signature and cell proliferation were confirmed by GSEA analysis as more positively correlated pathways while inflammation and immune response related pathways were negatively correlated in SS. Transcriptomic characterization of eMPM reinforces the hypothesis that cell cycle, EMT and immune components could have an impact on eMPM outcome and could be exploited as therapeutic strategies.

Background: Pancreatic cancer (PC) is one of the most lethal malignancies worldwide. This study evaluated the prognostic role of serum alanine phosphatase (ALP) and gamma-glutamyl-transferase (GGT) in metastatic PC patients. Materials & methods: 153 patients with metastatic PC receiving first-line treatment with nab-paclitaxel/gemcitabine were retrospectively enrolled in a multicenter study and stratified according to ALP (≤ or >260 U/l) and GGT (≤ or >45.5 U/l) levels. Results: Improved overall survival was recorded in patients with GGT levels ≤45.5 U/l (p < 0.05). In patients with liver metastasis, overall survival was significantly lower in patients with high ALP (p = 0.01) and GGT (p = 0.02). Conclusion: High levels of ALP and GGT were related to a poor prognosis in PC patients with liver metastasis receiving nab-paclitaxel/gemcitabine.

AIM:DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival.METHODS:A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status.RESULTS:Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS.CONCLUSIONS:The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.

TYPE: Case Report TOPIC: Lung Cancer INTRODUCTION: EGFR mutated NSCLC benefits from targeted therapy with TKIs, however between 50 and 70% of the treated patients will progress and nearly half of these will develop resistance mutations such as T790M, for which a third-generation TKI is available. Progression to the central nervous system is sadly a common feature in NSCLC patients, it impacts their quality of life and the one of their family as well as the management of the disease. CASE PRESENTATION: A patient with IV stage adenocarcinoma of the lung progressed after 21 months of first-line anti-EGFR therapy and showed clear signs of neurological impairment, later cytologically confirmed as caused by a carcinosis on cerebrospinal fluid. Liquid biopsy detected the resistance mutation T790M and therapy was switched with the third generation TKI Osimertinib. The first instrumental re-evaluation reports a partial response, with a reduction of lesions dimensions both in the lung and at the brain-level involvement. DISCUSSION: The clinical evolution of this case study documents the efficacy in the nervous system of a third generation anti-EGFR agent, Osimertinib, in addition to the already documented efficacy in the control and management of pulmonary malignancies. Of particular note is the initial positive response after three months of therapy. The significant reduction at brain level may hopefully be a sign that the rapid evolution usually seen in this type of patient can be curbed CONCLUSIONS: This case study documents the efficacy of Osimertinib in the control and efficacy at the level of the central nervous system in an NSCLC stage IV patient. DISCLOSURE: Nothing to declare. KEYWORD: THIRD-GENERATION TKI

Purpose Monitoring mutation status in circulating free DNA (cfDNA) during target therapy could hold significant clinical importance in non-small cell lung cancer (NSCLC). Our aim is to establish if EGFR mutational status change on cfDNA has predictive value that can impact clinical management of NSCLC patients care. Methods This study included 30 patients with EGFR-mutated NSCLC. Blood samples were collected at diagnosis (T0) and in 19 patients during therapy (T1). Results Concordance between T0 and T1 EGFR mutation status for patients evaluable for both samples ( n = 19) was 79%, with a sensitivity of 100% (95% CI: 55.5–100.0) and specificity of 60.0% (95% CI: 26.2–86.8). For the patients in oncological therapy with targeted drug and with T1 sample available ( n = 18), survival outcomes were evaluated. For both mutation-negative T0 and T1 patients, 12-month progression-free survival (PFS) was 66.7% (95% CI: 27.2–100.0) and 12-month overall survival (OS) was 100% (95% CI: 1.00–1.00); for patients mutated both at T0 and T1, PFS was 22.2% (95% CI: 6.5–75.4%) and OS was 55.6% (95% CI: 20.4–96.1%). Conclusion EGFR mutation status can be assessed using cfDNA for routine purposes and longitudinal assessment of plasma mutation is an easy approach to monitor the therapeutic response or resistance onset.

Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.

Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.

PURPOSE:mTOR inhibitor everolimus is used for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC). No reliable predictive biomarker of response is available. Following evidences from other solid tumors, we aimed to assess the association between treatment-associated immune system features and everolimus activity. METHODS:We retrospectively explored a correlation with the therapeutic activity of everolimus and tumor-associated immune pathways with ingenuity pathway analysis (IPA), neutrophil-to-lymphocyte ratio (NLR), circulating lymphocytes, and endothelial cells (CECs) in 3 different HR+ mBC studies, including the BALLET phase IIIb study. RESULTS:The circulating levels of CD3+/CD8+, CD3+/CD4+, and overall T lymphocytes were higher in responders versus non-responders at baseline (p = 0.017, p < 0.001, p = 0.034) and after treatment (p = 0.01, p = 0.003, p = 0.023). Reduced CECs, a tumor neoangiogenesis marker, were observed in responders after treatment (p < 0.001). Patients with low NLR (≤ 4.4) showed a better progression-free survival compared to patients with high NLR (> 4.4) (p = 0.01). IPA showed that the majority of immunity-related genes were found upregulated in responders compared to non-responders before treatment, but not after. CONCLUSIONS:Lymphocytes subpopulations, CECs and NLR could be interesting biomarkers predictive of response to everolimus-based regimens, potentially useful in daily clinical practice to select/monitor everolimus-based treatment in mBC. Further studies to confirm such hypotheses are warranted.

A key tool for monitoring breast cancer patients under neoadjuvant treatment is the identification of reliable predictive markers. Ki67 has been identified as a prognostic and predictive marker in ER-positive breast cancer. Ninety ER-positive, HER2 negative locally advanced breast cancer patients received letrozole (2.5 mg daily) and cyclophosphamide (50 mg daily) with/without Sorafenib (400 mg/bid daily) for 6 months before undergoing surgery. Ki67 expression and tumor size measured with caliber were determined at baseline, after 30 days of treatment and at the end of treatment. Patients were assigned to a clinical response category according to Response Evaluation Criteria in Solid Tumors, both at 30 days and before surgery and further classified as high-responder and low-responder according to the median variation of Ki67 values between biopsy and 30 days and between biopsy and surgery time. The predictive role of Ki67 and its changes with regard to clinical response and survival was analyzed. No differences in terms of survival outcomes emerged between the arms of treatment, while we observed a higher percentage of women with progression or stable disease in arm with the combination containing Sorafenib (20.5% vs 7.1%, p = 0.06). Clinical complete responders experienced a greater overall variation in Ki67 when compared with partial responders and patients with progressive/stable disease (66.7% vs 30.7%, p = 0.009). High responders showed a better outcome than low responders in terms of both disease-free survival (p = 0.009) and overall survival (p = 0.002). ΔKi67 score evaluated between basal and residual tumor at definitive surgery showed to be highly predictive of clinical complete response, and a potential parameter to be used for predicting disease-free survival and overall survival in luminal breast cancer treated with neoadjuvant endocrine-based therapy.

Neutropenia is a common side effect associated with nab-paclitaxel gemcitabine (Nab-Gem) therapy. We retrospectively investigated the association between neutropenia induced by first-line Nab-Gem and survival in metastatic pancreatic carcinoma patients. Metastatic pancreatic patients treated with first-line Nab-Gem were included in this retrospective analysis. Neutropenia was categorized using the National Cancer Institute Common Toxicity Criteria scale. Outcome measures were overall survival (OS), progression-free survival (PFS) and response rate. 115 patients were analyzed. Median PFS was 7 months (95% CI 5–8) for patients with grade ≥ 3 neutropenia and 6 months (95% CI 5–6) for patients with grade < 3 neutropenia [p = 0.08; hazard ratio (HR 0.68)]. Median OS was 13 months (95% CI 10–18) for patients with grade ≥ 3 neutropenia and 10 months (95% CI 8–13) for patients with grade < 3 neutropenia (p = 0.04; HR 0.44). In multivariate analysis, the occurrence of grade ≥ 3 neutropenia showed a statistically significant association with OS (HR 0.62; 95% CI 0.09–0.86; p = 0.05). Nab-Gem-induced neutropenia is associated with longer survival in metastatic pancreatic cancer patients.

Malignant pleural mesothelioma (MPM) is a rare and aggressive form of tumour. Some mesotheliomas have been proven to be highly immunogenic. Here, we investigated the correlation between tumour infiltrating lymphocytes (TILs) or programmed cell death ligand 1 (PD-L1) expression with overall survival (OS) in patients with MPM. 62 Paraffin-embedded formalin fixed (PEFF) samples were analysed for TILs and PD-L1 expression. Patients were divided in 4 groups according to a cut-off of the percentage of TILs found per sample as measured by immunohistichemistry: “0” or absent (between 0 and 5%), “1” or low (between 6 and 25%), “2” or moderate (between 26 and 50%) and “3” or high (between 51 and 75%). OS was then correlated with different TILs’ expression patterns. Moreover, PD-L1 expression was assessed within the tumour as well as in the adjacent stroma on the same samples. Higher expression of peritumoral TILs (Group 2 + 3) versus Group 0 and 1 correlated with improved OS (p-value = 0.02). On the contrary PD-L1 expression seemed to be inversely correlated with clinical outcomes, even in the absence of statistical significance (HR 1.76; p = 0.083 95% IC 0.92–3.36 in areas within the tumour; HR 1.60; p = 0.176 95%; IC 0.80–3.19 in areas within the stroma). No relationship between TILs and PD-L1 expression was identified. Our research supports the use of TILs and PD-L1 expression as potential outcome predictors in patients with MPM. The use of TILs and PD-L1 as biomarkers for checkpoint inhibitors’ efficacy warrants future investigation.

ImmunotherapyVol. 11, No. 5 EditorialFree AccessOptimal primary end point in Phase II trials of immune checkpoint inhibitors for advanced solid cancers: an evolving issueGiandomenico Roviello, Daniele Generali & Anna IanzaGiandomenico Roviello*Author for correspondence: E-mail Address: giandomenicoroviello@hotmail.it Translational Oncology Unit, Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139 Florence, Italy, Daniele Generali Department of Medical, Surgery & Health Sciences, University of Trieste, Trieste, Italy Breast Cancer Unit & Translational Research Unit, ASST Cremona, Cremona, Italy & Anna Ianza Department of Medical, Surgery & Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, ItalyPublished Online:20 Feb 2019https://doi.org/10.2217/imt-2018-0204AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: end pointsimmunotherapyPD-1PD-L1Phase IIImmune checkpoint inhibitors (ICIs) are a novel class of therapeutic agents whose peculiar mechanism of action, based on an activation of the immune system against tumor cells, has changed the management of several advanced solid tumors [1]. The use of the immune system against tumors is not a novelty in oncology field; in fact, IL-2, a cytokine produced by activated cytotoxic T lymphocytes, has shown a certain antitumor activity in melanoma and renal cell carcinoma but also in other solid tumors [2]. In addition, interferon (IFN) is another cytokine that has achieved US FDA approval as a single agent for the adjuvant therapy of stage III melanoma [3]. Finally, it has been suggested that response to chemotherapy and radiotherapy involves T-cell activation, corroborating the hypothesis that combining conventional chemotherapy with blocking of immune checkpoint would lead to an improvement in tumor response [3]. The evolution of the strategy of treatment that was started with the use of IL-2 and IFN lead to the development of the novel class of anticancer drugs known as ICIs. Ipilimumab was the first human monoclonal antibody that targets the cytotoxic T lymphocyte-associated antigen 4 receptor that showed an efficacy on advanced melanoma [4]. Consequently, the discovery of the antigen programmed cell death 1 (PD-1), a protein expressed on the surface of activated T cells, and its ligand PD-L1 (also known as B7-H1) expressed mainly in tumor cells as well as other immune cells, had led to a development of novel classes of ICIs: the anti-PD-1 and anti-PD-L1 antibodies that work by blocking the PD-1/PD-L1 pathway. The PD1 binding of its ligand PD-L1 results in inhibition of T-cells proliferation, so that anti-PD-1 or PD-L1 agents prevent this binding and consequently potentiate T-cell activity, including antitumor response. To date, two anti-PD-1 antibodies (nivolumab and pembrolizumab) have been approved for several solid tumors [5] and it is of September 2018 the news of cemiplimab US FDA approval for cutaneous squamous cell carcinoma. On the other hand, the anti-PD-L1s atezolizumab, avelumab and durvalumab are approved or under investigation [5]. Interestingly, the first approved ICI, ipilimumab, to date has been used only in melanoma or renal cell carcinoma [6]. An important point in favor of ICIs is the different toxicity profile compared with common chemotherapy, resulting in good compliance even for patients with advanced diseases. Finally, ICIs have been investigated in combination with chemotherapy in non-small-cell lung cancer [7] and with antiangiogenic agents in renal cell carcinoma [8].When a novel agent is approved in the field of oncology, there are generally two main issues. The first is identification of a surrogate marker for survival, required to select the appropriate primary end point for the early and further phases of drug development. This option permits quicker and less expensive studies. The second issue is the need of selective biomarkers to better tailor the therapeutic agent. For example, the guideline for decreasing of 50% of more of the serum prostate-specific antigen value in patients with prostate cancer is usually used as a valid surrogate for survival and to identify in an earlier phase of treatment those patients who are not responsive to anticancer agents and who may benefit from a change in therapy [9,10]. For what concerns ICI treatments, the role of PD-L1 expression as a marker of response remains controversial [11], although it has been used as a selective criterion for pembrolizumab treatment of patients with non-small-cell lung cancer. In general, the clinical evaluation of the activity and efficacy of a conventional or biological cancer treatment is assessed by change in tumor burden. The main criteria used for the evaluation of these changes are the Response Evaluation Criteria in Solid Tumors (RECIST), which are used not only in experimental but also in clinical practice as a guide to continue or discontinue a treatment [12]. According to the RECIST criteria, the rate of total patients with a complete response or a partial response defines the objective tumor response rate (ORR). The ORR is generally used as primary end point in Phase II trials, hence the choice of ORR as the preferred surrogate parameter for overall survival (OS). The Phase II trial is generally the first step to evaluate the efficacy of an anticancer agent. Based on this universal approach for drug development, the design of a typical Phase II trial in immunotherapy is single arm with a moderate number of patients enrolled, with ORR as the primary end point. Unfortunately, researchers were faced with a unique event that characterizes the pattern of response and progression of ICIs compared with those of conventional chemotherapy or biological/molecular-targeted therapies: the pseudo-progression. This event is characterized by the development of new lesions or an increase in existing lesions, which is not strictly related to a resistance to treatment [13] but rather to an infiltration of immune cells triggered by ICIs [14,15]. As matter of fact, the correlation between ORR and survival in Phase II ICI trial seems to be weakened by pseudo-progression, an expected event in this kind of therapy, and by the lack of a careful selection of the patient. Indeed, a more accurate selection method would better determine an ulterior lowering of the numbers; on the other hand, it should also discriminate a greater effectiveness of agents. In this context, a recent meta-analysis [16] compared the primary end points of 87 Phase II trials, weighing the strength of the correlation of the surrogate parameter with 6 months progression-free survival (PFS) and 12-month OS rate using a unique prediction model of correlation. They found that 60% of Phase II trials had ORR as the primary end point, but that ORR correlated poorly with OS. However, 6-month PFS correlates relatively strongly with the 12-month OS rate and is proposed as a preferred parameter to be used in Phase II studies. In addition, Kaufman et al. performed a systematic literature review with meta-analysis to assess the correlation of classical clinical end points used in clinical trial such as PFS, ORR or disease control rate and their use for surrogacy of OS. A total of 27 randomized controlled trials were evaluated for a total of more than 10,000 patients. The rate of patients with tumor response and PFS hazard ratio (HR) showed a weak correlation with survival; however, 6-month PFS HR was predictive of survival. Interestingly, PFS HR at 6 months was highly predictive of survival in the subgroup of patients treated with single-agent ICI, but was weakly predictive in the pooled analysis. In line with the two above literature analysis [16,17], a recent robust meta-regression of 24 trials, for a total of 11,894 patients, aims to assess the role of the tumor response rate (RR) after ICI-based therapy as a potential surrogate end point of PFS and OS confirmed a weak correlation between RR and OS [5].To try to avoid the limitations of ORR during ICI-based therapy, a modified version of the RECIST criteria has been recently proposed, immune-related response criteria (iRECIST) and immune-modified response criteria (imRECIST), in response to the need for an appropriate scale to evaluate and distinguish pseudo-progression from real progression of disease [18]. Nevertheless, only 6% of the included trials considered iRECIST, either as a primary or secondary end point [16]. The recurrence rate of pseudo-progressions in ICI-treated tumor strictly depends on the scale used to measure the response, and onset occurs and is completely concluded on average in a 1-year period [19].All these data underscore the limitations of Phase II trials and the challenges involved in translating early promising clinical results from Phase II trials in efficacy to survival of Phase III studies. In fact, promising Phase II trials have not translated into successful Phase III trials for some ICIs [20]. Nevertheless, further studies are ongoing to explore the role of ICIs in combination with chemotherapy or antiangiogenic agents. For these types of studies, the optimal primary end points in early clinical investigations are not well defined. Although it could be speculated that potential future end points of Phase II studies for ICIs may include classical clinical end points in combination with newer end points such as stability in overall tumor burden, sustained reduction or durable response rate, to date, very few Phase II studies have used this combination of end points and further investigations are required to define its role.ConclusionICIs have revolutionized the treatment scenario of several solid tumors. However, there is urgent need to identify dedicated end points in early clinical Phase II studies with ICIs. This identification could better and more cost-effectively drive the selection of the most accurate agent to be used in randomized Phase III trials. At this time point, it seems that the phenomenon of false progression and the difficulties in selecting and finding the appropriate population of patients indirectly affect the further approval of compounds for the successive phases of research. Considering that ORR is the most used surrogate end point and that correlates poorly with survival, other end points such as 6-month PFS could be used as surrogate markers for survival in future Phase II ICI trials.AcknowledgmentsAuthors thank Elsevier Language Editing Services for the English editing of this manuscript.Financial & competing interests disclosuresThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Medical writing support was provided by Elsevier Language Editing Services and was self-funded by authors.References1 Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 11; 369(2), 122–133 (2013).Crossref, Medline, CAS, Google Scholar2 Roviello G, Zanotti L, Correale P et al. Is still there a role for IL-2 for solid tumors other than melanoma or renal cancer? Immunotherapy 9(1), 25–32 (2017).Link, CAS, Google Scholar3 Lee S, Margolin K. Cytokines in cancer immunotherapy. Cancers 133(4), 3856–3893 (2011).Crossref, Google Scholar4 Tarhini AA, Iqbal F. CTLA-4 blockade: therapeutic potential in cancer treatments. Onco Targets Ther. 24(3), 15–25 (2010).Crossref, Google Scholar5 Roviello G, Andre F, Venturini S et al. Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: a meta-regression of randomised prospective studies. Eur. J. Cancer 86, 257–265 (2017).Crossref, Medline, CAS, Google Scholar6 Martin-Liberal J, Ochoa de Olza M, Hierro C, Gros A, Rodon J, Tabernero J. The expanding role of immunotherapy. Cancer Treat. Rev. 54, 74–86 (2017).Crossref, Medline, CAS, Google Scholar7 Zhang Y, Zhou H, Zhang L. Which is the optimal immunotherapy for advanced squamous non-small-cell lung cancer in combination with chemotherapy: anti-PD-1 or anti-PD-L1? J. Immunother. Cancer 6(1), 135 (2018).Crossref, Medline, Google Scholar8 Bracarda S, Porta C, Sabbatini R, Rivoltini L. Angiogenic and immunological pathways in metastatic renal cell carcinoma: a counteracting paradigm or two faces of the same medal? The GIANUS review. Crit. Rev. Oncol. Hematol. S1040–S8428(18), 30141–0 (2018).Google Scholar9 Roviello G. Role of PSA response as a marker for efficacy of patients with castration-resistant prostate cancer treated with novel hormonal therapies. Int. J. Biol. Mark. 33(1), 132–133 (2018).Crossref, Medline, Google Scholar10 Francini E, Petrioli R, Rossi G, Laera L, Roviello G. PSA response rate as a surrogate marker for median overall survival in docetaxel-based first-line treatments for patients with metastatic castration-resistant prostate cancer: an analysis of 22 trials. Tumour Biol. 35(11), 10601–10607 (2014).Crossref, Medline, CAS, Google Scholar11 Kluger HM, Zito CR, Turcu G et al. PD-L1 studies across tumor types, its differential expression and predictive value in patients treated with immune checkpoint inhibitors. Clin. Cancer Res. 23(15), 4270–4279 (2017).Crossref, Medline, CAS, Google Scholar12 Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).Crossref, Medline, CAS, Google Scholar13 Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J. Clin. Oncol. 33(31), 3541–3543 (2015).Crossref, Medline, CAS, Google Scholar14 Wolchok JD, Hoos A, O'Day S et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15(23), 7412–7420 (2009).Crossref, Medline, CAS, Google Scholar15 Hodi FS, Butler M, Oble DA et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc. Natl Acad. Sci. USA 105(8), 3005–3010 (2008).Crossref, Medline, CAS, Google Scholar16 Ritchie G, Gasper H, Man J et al. Defining the most appropriate primary end point in Phase II trials of immune checkpoint inhibitors for advanced solid cancers: a systematic review and meta-analysis. JAMA Oncol. 4(4), 522–528 (2018).Crossref, Medline, Google Scholar17 Kaufman HL, Schwartz LH, William WN Jr et al. Evaluation of classical clinical end points as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis. J. Cancer Res. Clin. Oncol. 144(11), 2245–2261 (2018).Crossref, Medline, CAS, Google Scholar18 Seymour L, Bogaerts J, Perrone A et al. RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 18(3), e143–e152 (2017).Crossref, Medline, Google Scholar19 Kurra V, Sullivan RJ, Gainor JF, Hodi FS, Gandhi L, Sadow CA. Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes. J. Clin. Oncol. 34(no. 15_suppl.), S6580–S6580 (2016).Crossref, Google Scholar20 Gopalakrishnan D, Koshkin VS, Ornstein MC, Papatsoris A, Grivas P. Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook. Ther. Clin. Risk Manag. 14, 1019–1040 (2018).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 11, No. 5 Follow us on social media for the latest updates Metrics History Received 12 December 2017 Accepted 21 January 2019 Published online 20 February 2019 Published in print April 2019 Information© 2019 Future Medicine LtdKeywordsend pointsimmunotherapyPD-1PD-L1Phase IIAcknowledgmentsAuthors thank Elsevier Language Editing Services for the English editing of this manuscript.Financial & competing interests disclosuresThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Medical writing support was provided by Elsevier Language Editing Services and was self-funded by authors.PDF download

Breast cancer (BC) is the second most common cause of cancer-related deaths in women worldwide. The availability of reliable biomarkers of response/resistance to cancer treatments would benefit patients and clinicians allowing for a better selection of BC patients most likely to respond to a specific treatment. Phosphatidylinositol 3-kinase (PI3K) enzymes are involved in numerous cellular- functions and processes. The gene encoding for PI3K catalytic subunit p110α is mutated in 20-40% of BC. We performed a meta-analysis of the current literature on randomized clinical trials, investigating the role of PIK3CA mutational status as prognostic factor, and predictor of response to anti-cancer treatments. Overall 1929 cases were included. The pooled analysis confirmed that the presence of a PIK3CA mutation represents an independent negative prognostic factor (HR = 1.67, 95%CI: 1.15-2.43; P = 0.007) in BC, as previously reported. As PI3K signaling is also a result of other pathways' hyperactivation, further investigation of potential biomarkers able to predict likelihood of response to anti-PI3K/mTOR, anti-HER2, and other TKRs is warranted in future randomized clinical trials.

INTRODUCTION:Renal cell carcinoma (RCC) accounts for 2-3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC.AREAS COVERED:Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma.EXPERT OPINION:Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy.

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients' specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

Breast cancer (BC) is the most common cancer in women worldwide. One in eight women will develop the disease in her lifetime. Notwithstanding the incredible progress made in this field, BC still represents the second most common cause of cancer-related death in women. Targeted drugs have revolutionised breast cancer treatment and improved the prognosis as well as the life expectancy of millions of women. However, the phenomenon of primary and secondary pharmacological resistance is becoming increasingly evident, limiting the efficacy of these agents and calling for a better in-depth knowledge and understanding of the biology as well as the biochemical crosstalk underlying the disease. The advent of laboratory technologies in the clinical setting such as the routine use of next generation sequencing has allowed identification of new genetic alterations as well as providing a precise picture of the molecular landscapes of each tumour. Consequently, new specific therapeutic approaches are becoming available to minimise or delay the occurrence of resistance. In this review, we analyse the latest research and news from the clinical development side for each BC subtype.

In regard to the article “Targeting BAP1: a new paradigm for mesothelioma” by Laurel M. Schunselaar et al., which appeared in Lung Cancer (2017); 109: 145–146, discussing BAP1 pathway as a promising therapeutic target for treating mesotheliomas, we would like to discuss the need for randomized clinical trials evaluating the targeted therapies in this disease.

Malignant mesothelioma is a rare and aggressive form of cancer affecting the mesothelium. This mainly occupational disease is becoming more common in those countries where asbestos has been used for industrial applications. Notwithstanding the progress made in the field, patients do not survive more than 12 months on average with standard treatment. With the advent of next generation sequencing, it is now possible to study the mutational landscape of each tumor with the aim of identifying the genetic aberrations driving tumorigenesis. This review encompasses the latest research in the field, with particular attention to new chemotherapy combinatorial regimens, molecular targets and immunotherapies, providing a comprehensive picture of the current and future treatment options for malignant mesothelioma patients.